Compositions and methods for controlling the flux of a drug from a transdermal drug delivery systems

ABSTRACT

A blend of at least two polymers in combination with a drug provides a pressure-sensitive adhesive composition for a transdermal drug delivery system in which the drug is delivered from the pressure-sensitive adhesive composition and through dermis when the pressure-sensitive adhesive composition is in contact with human skin.

This application claims the benefit of provisional application60/616,862 filed Oct. 8, 2004, which is hereby incorporated by referencein its entirety.

FIELD OF THE INVENTION

This invention relates generally to transdermal drug delivery systems,and more particularly to pharmaceutically acceptable adhesive matrixcompositions. The invention additionally relates to transdermal drugdelivery systems providing substantially zero order drug releaseprofiles for an extended period of time of up to seven days or longer.

BACKGROUND OF THE INVENTION

The present invention relates to transdermal delivery systems, theirmethod of making and method of use. In particular, the present inventionis directed to a transdermal drug delivery system for the topicalapplication of one or more active agents contained in one or morepolymeric and/or adhesive carrier layers, proximate to a non-drugcontaining polymeric and/or adhesive coating that is applied to eitherthe transdermal system's backing or release liner. The adhesive coatedbacking or release liner may be processed or manufactured separatelyfrom the polymeric and/or adhesive drug carrier layers when drug loss orother system concerns are prevalent, and combined prior to topicalapplication. The drug delivery rate and profile can be furthercontrolled by adjusting certain characteristics of the polymers and/oradhesives themselves or of the method of making the system, relative tothe active agent's properties in this transdermal system.

BACKGROUND OF THE INVENTION

The use of a transdermal drug delivery system as a means foradministering therapeutically effective amounts of an active agent iswell known in the art. Transdermal devices or systems can be categorizedin many different ways, but those commonly called transdermal patches,incorporate the active agent into a carrier, usually a polymeric and/ora pressure-sensitive adhesive formulation.

Many factors influence the design and performance of such drug deliverydevices, such as the individual drugs themselves, the physical/chemicalcharacteristics of the system's components themselves and theirperformance/behavior relative to other system components once combined,external/environmental conditions during manufacturing and storagethereafter, the properties of the topical site of application, thedesired rate of drug delivery and onset, the drug delivery profile, andthe intended duration of delivery. Cost, appearance, size and ease ofmanufacturing are also important considerations. The ability to delivera therapeutically effective amount of the drug in accordance with theintended therapy or treatment is the goal.

The simplest in design is one in which the drug is incorporated into apressure-sensitive adhesive carrier layer, each surface of which isaffixed to a polymeric film/layer—one serving as the backing (to anchorthe carrier layer and control passage of environmental influences in andsystem components out during use) and the other serving as a removableliner (to protect the carrier layer prior to use but removed upontopical application of the carrier layer). However, when addressing allthe design and performance factors and considerations to achieve thegoal, this system alone cannot always provide the best method.

In this regard, a drug's delivery rate is affected by its degree ofsaturation and solubility in the carrier composition. Depending on theactive agent itself or the dosage necessary to be therapeuticallyeffective, the amount of drug needed to be incorporated into a single,adhesive carrier or matrix composition (i.e., drug loading) canadversely affect or be adversely affected by, such carrier or matrix.

Drug carrier compositions typically require one or more processingsolvents, usually organic solvents, in which to incorporate the activeagent and/or allow the polymeric/adhesive carrier to be more easilycoated onto a backing or release liner. Removal of such solvents isnecessary for avoiding problems associated with residual solventamounts, such as irritation at the topical site of application, drugdegradation, drug instability, loss of adhesive or cohesive propertiesimpacting attachment of the system to the user and loss of desireddelivery amount or rate. Solvent removal requires that elevatedtemperatures be applied to the carrier composition to evaporate suchsolvents. But at the same time, removal of solvents by use of elevatedtemperatures can also remove or evaporate other desirable components,such as the active agent and drug permeation enhancers. Their loss caneven occur at temperatures below which such components may otherwisevolatilize by virtue of their interaction with each other and with theother carrier components (relative volatility or reactivity).

Transdermal carrier compositions based on acrylic pressure-sensitiveadhesive polymers are often preferred for their ability to incorporateor solubilize many drugs. In order to provide for adequate wearproperties and drug release from the composition, acrylic-basedpressure-sensitive adhesives are typically polymerized with functionalmonomers to provide functional groups on the acrylic-based adhesive. Aproblem associated with the use of such acrylic-based polymers withfunctional groups is that due to the generally high solubility of thedrug, a large amount of drug generally must be incorporated into thecomposition to saturate it and provide an adequate drug release to theskin of the user. In use with low molecular weight drugs or controlledsubstances, the loss of the drug in the manufacturing process again canbe a significant problem.

Attempts have been made to utilize rate controlling membranes and/ormultiple layers, and to dissolve or suspend certain drugs inthermoplastic type carrier compositions without the use of solvents.These drug delivery devices generally do not allow a great amount offlexibility in effectively controlling the release rate of a variety ofdrugs, which in turn also severely limits their therapeutic application,and are expensive or burdensome to manufacture. Moreover, multipleadhesive layers are often required to affix the other layers ormembranes to each other, and/or to the site of topical application.

Thus, it would therefore be desirable to provide a system for use withmany types of drugs, in which the permeation rate and profile can beeasily adjusted while providing an active agent-containing carriercomposition formulated in a simple and cost effective manner.

SUMMARY OF THE INVENTION

Based upon the foregoing, it is an object of the present invention toovercome the limitations of the prior transdermal systems, and toprovide a transdermal drug delivery system which allows selectivemodulation of drug permeation and delivery rates and profiles.

Another object is to provide a transdermal system, which is simple andinexpensive to manufacture, while preventing or minimizing drug lossand/or other volatile components in the composition. The presentinvention provides a transdermal drug delivery system for the topicalapplication of one or more active agents contained in one or morepolymeric and/or adhesive carrier layers, proximate to a non-drugcontaining polymeric and/or adhesive coating that is applied to eitherthe transdermal system's backing or release liner, manufactured tooptimize drug loading while providing desirable adhesion to skin ormucosa as well as providing modulation of the drug delivery and profile.

The invention is further directed to a transdermal delivery systemcomprising a backing composite comprising a non-drug containingpolymeric and/or adhesive coating affixed or applied to adrug-impermeable layer. An active agent carrier layer comprising apressure-sensitive adhesive composition and a drug incorporated therein,which may also contain low boiling point or volatile components such aspermeation enhancers, is affixed to the backing composite. The polymericcoating is designed to provide control of permeation rate, onset andprofile of the active agent from the system. The agent-carriercomposition may comprise one or more layers. The agent-carriercomposition may comprise at least one layer formed of a blend of atleast one acrylic-based polymer and at least one silicone-based polymer,to serve as a pressure-sensitive adhesive composition for applying thesystem to the dermis, or a blend of acrylic-based polymers. The non-drugcontaining acrylic-based or other polymer coating designed to interactwith the drug composition layer(s).

The invention is also directed to compositions and methods ofcontrolling drug delivery rates, onset and profiles of at least oneactive agent in a transdermal delivery system, comprising the use of anon-drug containing acrylic-based polymer and/or adhesive coating onesurface of which is applied to either the transdermal system's backingor release liner and the other surface is affixed to a drug containingcarrier composition layer, wherein the delivery rate, onset of delivery(lag time) and delivery profile of a drug may be selectively modulatedby one or more of (a) increasing or decreasing the thickness or coatweight of the acrylic-based polymer and/or adhesive coating per cm² asapplied to the backing or release liner of the system or (b)manipulating the moiety or functionality of the acrylic-based polymerand/or adhesive coating. Either the non-drug containing coating or thecarrier composition must also be a pressure-sensitive adhesive when usedas area of attachment to the skin or mucosa of the user. The drugcarrier composition may be comprised of (a) one or more acrylic-basedpolymers having one or more functionality or (b) one or moresilicone-based polymers having one or more silanol contents (capping)and/or resin to polymer ratios, alone or in combination, and are presentin proportions to provide a desired solubility for the drug. Furthermanipulation of drug delivery, onset and profiles can be achieved byvarying the concentrations of the drug in the drug-loaded carrier.

For a better understanding of the present invention, together with otherand further objects thereof, reference is made to the followingdescription, taken in conjunction with the accompanying drawings, andits scope will be pointed out in the appending claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic cross-sectional view of a transdermal deliverydevice according to an embodiment of the invention prior to use.

FIG. 2 shows a schematic cross-section of the agent-carrier assembly andbacking assembly according to the embodiment of the present invention asshown in FIG. 1, prior to lamination together.

FIG. 3 is a graphic representation of the effects on drug delivery,onset and profile of estradiol with different functionalities/moietiesof acrylic-based adhesives in the polymeric coating.

FIG. 4 is a graphic representation of the effects on drug delivery,onset and profile of estradiol with varying coat weights of anacrylic-based adhesive coating.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following description, embodiments of the invention are setforth, and terms are used in describing such embodiments, wherein:

The term “topical” or “topically” is used herein in its conventionalmeaning as referring to direct contact with an anatomical site orsurface area on a mammal including skin, teeth, nails and mucosa.

The term “mucosa” as used herein means any moist anatomical membrane orsurface on a mammal such as oral, buccal, vaginal, rectal, nasal orophthalmic surfaces. Similarly, “skin” is meant to include mucosa, whichfurther includes oral, buccal, nasal, rectal and vaginal mucosa.

The term “transdermal” refers to delivery, administration or applicationof a drug by means of direct contact with tissue, such as skin ormucosa. Such delivery, administration or application is also known aspercutaneous, dermal, transmucosal and buccal.

As used herein, the terms “blend” and “mixture” are used herein to meanthat there is no, or substantially no, chemical reaction or crosslinking(other than simple H-bonding) between the different polymers in thepolymer matrix. However, crosslinking between a single polymer componentis fully contemplated to be within the scope of the present invention.

The term “adhesive” means a substance, inorganic or organic, natural orsynthetic that is capable of surface attachment at the intended topicalapplication site by itself or functions as an adhesive by admixture withtackifiers, plasticizers, cross-linking agents or other additives. Inthe most preferred embodiment, the carrier of the present invention is a“pressure-sensitive adhesive” which refers to a viscoelastic materialwhich adheres instantaneously to most substrates with the application ofvery slight pressure and remains permanently tacky. A polymer or dermalcomposition is a pressure-sensitive adhesive within the meaning of theterm as used herein if it has the adhesive properties of apressure-sensitive adhesive per se or functions as a pressure-sensitiveadhesive by admixture with tackifiers, plasticizers, cross-linkingagents or other additives.

As used herein, a “polymer composition of two or more polymers” isdefined as a physical blend of at least two polymers and can include 3or more polymers. The two or more polymers may include the acrylic-basedpolymers described herein and can optionally include other polymersdiscussed more fully below.

The term “acrylic-based” polymer is defined as any polyacrylate,polyacrylic, acrylate and acrylic polymer. The acrylic-based polymerscan be any of the homopolymers, copolymers, terpolymers, and the like ofvarious acrylic acids or esters. The acrylic-based polymers useful inpracticing the invention are polymers of one or more monomers of acrylicacids and other copolymerizable monomers. The acrylic-based polymersalso include copolymers of alkyl acrylates and/or methacrylates and/orcopolymerizable secondary monomers. Acrylic-based polymers withfunctional groups as described more fully below, are copolymerized withfunctional monomers.

As used herein, “functionality” is broadly defined as a measure of thetype and quantity of functional groups that a particular acrylic-basedpolymer has.

As used herein, “functional monomers or groups,” are monomer units inacrylic-based polymers which have reactive chemical groups which modifythe acrylic-based polymers directly or provide sites for furtherreactions. Examples of functional groups include carboxyl, epoxy andhydroxy groups.

As used herein “non-functional acrylic-based polymer” is defined as anacrylic-based polymer that has no or substantially no functionalreactive moieties present in the acrylic. These are generally acrylicesters which can be copolymerized with other monomers which do not havefunctional groups, such as vinyl acetate.

The term “carrier” as used herein refers to any non-aqueous materialknown in the art as suitable for transdermal drug deliveryadministration, and includes any polymeric material into which an activeagent may be solubilized in combination or admixture with the otheringredients of the composition. The polymeric materials preferablycomprise adhesives and, in particular, pressure-sensitive adhesives. Thecarrier material is typically used in an amount of about 40% to about95%, and preferably from about 50% to about 80%, by weight based on thedry weight of the total carrier composition.

The term “carrier composition” may also refer to enhancers, solvents,co-solvents and other types of additives useful for facilitatingtransdermal drug delivery.

The carrier compositions of the present invention can also contain oneor more non-aqueous solvents and/or co-solvents. Such solvents and/orco-solvents are those known in the art, and are non-toxic,pharmaceutically acceptable substances, preferably non-aqueous liquids,which do not substantially negatively affect the adhesive properties orthe solubility of the active agents at the concentrations used. Thesolvent and/or co-solvent can be for the active agent or for the carriermaterials, or both.

Suitable solvents include volatile processing liquids such as alcohols(e.g., methyl, ethyl, isopropyl alcohols and methylene chloride);ketones (e.g., acetone); aromatic hydrocarbons such as benzenederivatives (e.g., xylenes and toluenes); lower molecular weight alkanesand cycloalkanes (e.g., hexanes, heptanes and cyclohexanes); andalkanoic acid esters (e.g., ethyl acetate, n-propyl acetate, isobutylacetate, n-butyl acetate isobutyl isobutyrate, hexyl acetate,2-ethylhexyl acetate or butyl acetate); and combinations and mixturesthereof. Other suitable co-solvents include polyhydric alcohols, whichinclude glycols, triols and polyols such as ethylene glycol, diethyleneglycol, propylene glycol, dipropylene glycol, trimethylene glycol,butylene glycol, polyethylene glycol, hexylene glycol, polyoxethylene,glycerin, trimethylpropane, sorbitol, polyvinylpyrrolidone, and thelike. Alternatively, co-solvents may include glycol ethers such asethylene glycol monoethyl ether, glycol esters, glycol ether esters suchas ethylene glycol monoethyl ether acetate and ethylene glycoldiacetate; saturated and unsaturated fatty acids, mineral oil, siliconefluid, lecithin, retinol derivatives and the like, and ethers, estersand alcohols of fatty acids. As will be described in more detailhereafter, the solvents or co-solvents used in accordance with theinvention are desirably a low volatile solvent that does not requireexcessive temperatures for evaporation thereof.

The term “solubilized” is intended to mean that in the carriercomposition there is an intimate dispersion or dissolution of the activeagent at the crystalline, molecular or ionic level, such that crystalsof the active agent cannot be detected using a microscope having amagnification of 25 times. As such, the active agent is consideredherein to be in “non-crystallized” form when in the compositions of thepresent invention. In some embodiments, however, the carrier compositionlayer includes a therapeutically effective amount of one or more solidcrystalline drugs incorporated therein.

As used herein “flux” is defined as the percutaneous absorption of drugsthrough the skin, and is described by Fick's first law of diffusion:J=−D(dC _(m) /dx),

where J is the flux in g/cm²/sec, D is the diffusion coefficient of thedrug through the skin in cm²/sec and dC_(m)/dx is the concentrationgradient of the active agent across the skin or mucosa.

As used herein, “therapeutically effective” means an amount of an activeagent that is sufficient to achieve the desired local or systemic effector result, such as to prevent, cure, diagnose, mitigate or treat adisease or condition, when applied topically over the duration ofintended use. The amounts necessary are known in the literature or maybe determined by methods known in the art, but typically range fromabout 0.1 mg to about 20,000 mg, and preferably from about 0.1 mg toabout 1,000 mg, and most preferably from about 0.1 to about 500 mg perhuman adult or mammal of about 75 kg body weight per 24 hours.

The term “about”, and the use of ranges in general whether or notqualified by the term about, means that the number comprehended is notlimited to the exact number set forth herein, and is intended to referto ranges substantially within the quoted range not departing from thescope of the invention.

The term “user” or “subject” is intended to include all warm-bloodedmammals, preferably humans.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice for testing of the present invention, the preferredmaterials and methods are described herein.

Referring to FIG. 1, the most preferred embodiment of the invention,transdermal drug delivery system 10 comprises a carrier compositionlayer 12 incorporating the active agent. Surface 14 of the adhesivecarrier composition layer 12 is affixed to release liner 15 to protectthe carrier layer prior to use but which is removed upon topicalapplication of the carrier layer to the skin or mucosa of the user. Anon-drug containing polymeric and/or adhesive coating 18 is affixed tobacking 20 on one surface, with the other surface being affixed tocarrier composition layer 12. Backing composite 16 comprises coating 18affixed to backing 20, which as described later, is made or processedseparately from carrier composition layer 12 affixed to release liner15.

Carrier composition layer 12 can comprise any polymer or adhesivegenerally known in the art for formulating a drug carrier composition,and include all of the non-toxic natural and synthetic polymers known orsuitable for use in transdermal systems including solvent-based, hotmelt and grafted adhesives, and may be used alone or in combinations,mixtures or blends. Examples include acrylic-based, silicone-based,rubbers, gums, polyisobutylenes, polyvinylethers, polyurethanes, styreneblock copolymers, styrene/butadiene polymers, polyether block amidecopolymers, ethylene/vinyl acetate copolymers, and vinyl acetate basedadhesives, and bioadhesives set forth in U.S. Pat. No. 6,562,363 whichis expressly incorporated by reference in its entirety.

The term “silicone-based” polymer is intended to be used interchangeablywith the terms siloxane, polysiloxane, and silicones as used herein andas known in the art. The silicone-based polymer may also be apressure-sensitive adhesive, with a polysiloxane adhesive prepared bycross-linking an elastomer, typically a high molecular weightpolydiorganosiloxane, with a resin, to produce a three-dimensionalsiloxane structure, via a condensation reaction in an appropriateorganic solvent. The ratio of resin to elastomer is a critical factorthat can be adjusted in order to modify the physical properties ofpolysiloxane adhesives. Sobieski, et al., “Silicone Pressure SensitiveAdhesives,” Handbook of Pressure-Sensitive Adhesive Technology. 2nd ed.,pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).Further details and examples of silicone pressure-sensitive adhesiveswhich are useful in the practice of this invention are described in thefollowing U.S. Pat. Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767,all expressly incorporated by reference in their entireties. Suitablesilicone pressure-sensitive adhesives are commercially available andinclude the silicone adhesives sold under the trademarks BIO-PSA® by DowCorning Corporation, Medical Products, Midland, Mich. (such as -2685,-3027, -3122, -4101, -4102, -4203, -4301, -4302, -4303, -4401-4403,-4501, -4503, -4602, -4603 and -4919). Capped silicones with high resincontent are preferred.

In the practice of the preferred embodiments of the invention, theacrylic-based polymer can be any of the homopolymers, copolymers,terpolymers, and the like of various acrylic acids. In such preferredembodiments, the acrylic-based polymer constitutes from about 2% toabout 95% of the total dry weight of the of the carrier composition, andpreferably from about 2% to about 90%, and more preferably from about 2%to about 85%, wherein the amount of the acrylic-based polymer isdependent on the amount and type of drug used.

The acrylic-based polymers usable in the invention are polymers of oneor more monomers of acrylic acids and other copolymerizable monomers.The acrylate polymers also include copolymers of alkyl acrylates and/ormethacrylates and/or copolymerizable secondary monomers or monomers withfunctional groups. By varying the amount of each type of monomer added,the cohesive properties of the resulting acrylate polymer can be changedas is known in the art. In general, the acrylate polymer is composed ofat least 50% by weight of an acrylate or alkyl acrylate monomer, from 0to 20% of a functional monomer copolymerizable with the acrylate, andfrom 0 to 40% of other monomers.

Acrylate monomers which can be used include acrylic acid, methacrylicacid, methyl acrylate, methyl methacrylate,butyl acrylate, butylmethacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate,2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate,2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate,and tridecyl methacrylate.

Functional monomers, copolymerizable with the above alkyl acrylates ormethacrylates, which can be used include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate.

Suitable acrylic-based polymers may also be a pressure-sensitiveadhesive which are commercially available and include the acrylic-basedadhesives sold under the trademarks Duro-Tak® by National Starch andChemical Corporation, Bridgewater, N.J. (such as 87-2287, -4098, -2852,-2196, -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085, -9088 and73-9301). Other suitable acrylic-based adhesives include those sold byCytec Surface Specialties, St. Louis, Mo., under the trademarks Gelva®Multipolymer Solution (such as 2480, 788, 737, 263, 1430, 1753, 1151,2450, 2495, 3087 and 3235) and those under the trademark Eudragit® byRoehm Pharma GmbH, Darmstadt, Federal Republic of Germany.

The carrier composition may comprise blends of acrylic-based polymers,silicone-based polymers and rubbers based upon their differingsolubility parameters, alone or in combination with other polymers, forexample polyvinylpyrrolidone, as more fully described in U.S. Pat. Nos.5,474,783; 5,656,286; 5,958,446; 6,024,976; 6,221,383; and 6,235,306;which are incorporated herein in their entirety. The amount of eachpolymer is selected to adjust the saturation concentration of the drugin the multiple polymer system, and to result in the desired rate ofdelivery of the drug from the system and through the skin or mucosa.

Combinations of acrylic-based polymers based on their functional groupsis also contemplated. Acrylic-based polymers having functional groupsare copolymers or terpolymers which contain in addition to nonfunctionalmonomer units, further monomer units having free functional groups. Themonomers can be monofunctional or polyfunctional. These functionalgroups include carboxyl groups, hydroxy groups, amino groups, amidogroups, epoxy groups, etc. Preferred functional groups are carboxylgroups and hydroxy groups. Preferred carboxyl functional monomersinclude acrylic acid, methacrylic acid, itaconic acid, maleic acid, andcrotonic acid. Preferred hydroxy functional monomers include2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethylacrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate,hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropylmethacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate,hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate,hydroxyhexyl methacrylate. Non-functional acrylic-based polymers caninclude any acrylic based polymer having no or substantially no freefunctional groups. The acrylic based polymer can include homopolymers,copolymers and terpolymers. The monomers used to produce the polymerscan include alkyl acrylic or methacrylic esters such as methyl acrylate,ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate,2-ethylbutyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate,nonyl acrylate, 2-ethylhexyl acrylate, decyl acrylate, dodecyl acrylate,tridecyl acrylate, glycidyl acrylate and the corresponding methacrylicesters.

Both the acrylic-based polymer having substantially no functional groupsand acrylic-based polymers having functional groups can optionallyinclude further modifying monomers. These modifying monomers can includeany conceivable monomer that is capable of undergoing vinylpolymerization. For example, the incorporation of styrene monomers canbe used to increase the glass transition temperature and are sometimesused to improve the cohesive strength. The copolymerization of vinylacetate monomers with acrylic esters are also used to form acrylic-basedpolymers. Ethylene can also be copolymerized with acrylic esters andvinyl acetate to give suitable acrylic-based polymers.

For example, a composition will require less of a functional acrylicthat contains 20% by weight of functional groups as opposed to one thatcontains 0.5% by weight of functional groups to achieve the same effectrequired for solubility and flux. Broadly speaking, the amount offunctional acrylic is generally within the range of about 1 to 99 weight% and preferably 5 to 95 weight %, more preferably 20 to 75 weight %,even more preferably 30 to 65 weight %, based on the total polymercontent of the transdermal composition. The amount of non-functionalacrylic or acrylic with a functional group which does not have as greatof an affinity for the drug, is within the range of about 99 to 1 weight%, preferably 95 to 5 weight %, more preferably 75 to 20 weight % andeven more preferably 30 to 65 weight %, based on the total polymercontent of the composition.

Further details and examples of acrylic-based adhesives, functionalmonomers, and polymers which have no functional groups and which aresuitable in the practice of the invention are described in Satas,“Acrylic Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology,2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, N.Y.(1989); “Acrylic and Methacrylic Ester Polymers,” Polymer Science andEngineering, Vol. 1, 2nd ed., pp 234-268, John Wiley & Sons, (1984);U.S. Pat. No. 4,390,520; and U.S. Pat. No. 4,994,267 all of which areexpressly incorporated by reference in their entireties.

The required proportions of acrylic-based or other polymers used aregenerally dependant on the specific drug, its desired delivery rate andthe desired duration of drug delivery. In general, proportions ofacrylic-based polymers also depend on the content of the functionalmonomer units in the functional acrylic.

When the drug carrier composition is intended to function as the facelayer, that is the layer that comes in contact with the topical site ofapplication as depicted in FIG. 1, it is preferable that the carriercomposition comprise a pressure-sensitive adhesive or bioadhesive.

In transdermal systems according to the invention, the drug carriercomposition is designed to provide selectable modulation of deliveryrates, onset and profiles of the drug when used in combination with anon-drug containing polymeric and/or adhesive coating that is applied toeither the transdermal system's backing or release liner. Minimizing orpreventing drug loss is also desirable when trying to deliver controlledsubstances and/or drugs that are easily volatilized and/or degradedduring the manufacture of the transdermal delivery system, for examplewhere there is high or excess drug concentration or loading in thecarrier composition or where the drug degrades from exposure toatmospheric air or oxygen.

Any molecular weight drug and its equivalent forms can be used in thepresent invention. The preferred drug is one that is hydrophilic and notrelatively volatile or reactive with the other carrier components, butwhich is incorporated into a carrier composition with certainco-solvents or enhancers preferred for use with such drugs that wouldbe, by their own properties or by virtue of their relative volatility orreactivity with the other carrier components, substantially unstable orsubstantially evaporated or driven-off at the temperatures generallyknown or used in the art to remove solvents during the manufacturingprocessing, typically in the range of 160° F. to 250° F.

The drugs and mixtures thereof can be present in the composition indifferent forms, depending on which yields the optimum deliverycharacteristics. Thus, in the case of drugs, the drug can be in its freebase or acid form, or in the form of salts, esters, amides, prodrugs,enantiomers or mixtures thereof, or any other pharmacologicallyacceptable derivatives, or as components of molecular complexes.

Any drug suitable for transdermal administration by methods previouslyknown in the art and by the methods of the present invention can be usedin the present invention, and further include such active agents thatmay be later established as drugs and are suitable for delivery by thepresent invention. These drugs include but are not limited to thosecategories and species of drugs set forth on page ther-1 to ther-28 ofthe Merck Index, 12th Edition Merck and Co. Rahway, N.J. (1999). Thisreference is incorporated by reference in its entirety. Exemplary ofdrugs that can be administered by the novel dermal drug delivery systeminclude, but are not limited to:

1. Central nervous system stimulants and agents such asDextroamphetamine, Amphetamine, Methamphetamine, D-Amphetamine,Phentermine, Methylphenidate and Nicotine.

2. Analgesics and/or Anti-Migraine such as Acetaminophen,Acetylsalicylic Acid, Buprenorphine, Codeine, Fentanyl, Lisuride,Salicylic Acid derivatives and Sumatriptan.

3. Androgen agents such as Fluoxymesterone, Methyl Testosterone,Oxymesterone, Oxymetholone, Testosterone and Testosterone derivatives.

4. Anesthetic agents such as Benzocaine, Bupivicaine, Cocaine,Dibucaine, Dyclonine, Etidocaine, Lidocaine, Mepivacaine, Prilocaine,Procaine and Tetracaine.

5. Anoretic agents such as Fenfluramine, Mazindol and Phentermine.

6. Anti-Bacterial (antibiotic) agents including Aminoglycosides,β-Lactams, Cephamycins, Macrolides, Penicillins, Polypeptides andTetracyclines.

7. Anti-Cancer agents such as Aminolevulinic Acid and Tamoxifen.

8. Anti-Cholinergic agents such as Atropine, Eucatropine andScopolamine.

9. Anti-Diabetic agents such as Glipizide, Glyburide, Glypinamide andInsulins.

10. Anti-Fungal agents such as Clortrimazole, Ketoconazole, Miconazole,Nystatin and Triacetin.

11. Anti-Inflammatory and/or Corticoid agents such as Beclomethasone,Betamethasone, Betamethasone Diproprionate, Betamethasone Valerate,Corticosterone, Cortisone, Deoxycortocosterone and Deoxycortocosterone,Acetate, Diclofenac, Fenoprofen, Flucinolone, Fludrocortisone,Fluocinonide, Fluradrenolide, Flurbiprofen, Halcinonide, Hydrocortisone,Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Ketorolac, Naproxen,Oxametacine, Oxyphenbutazone, Piroxicam, Prednisolone, Prednisone,Suprofen and Triamcinolone Acetonide.

12. Anti-Malarial agents such as Pyrimethamine.

13. Anti-Parkinson's and/or Anti-Alzhiemer's agents such asBromocriptine, 1-Hydroxy-Tacrine, Levodopa, Lisaride Pergolide,Pramipexole, Ropinirole, Physostigimine, Tacrine Hydrochloride andTeruride.

14. Anti-Psychotic and/or Anti-Anxiety agents such as Acetophenazine,Azapirones, Bromperidol, Chlorproethazine, Chlorpromazine, Fluoxetine,Fluphenazine, Haloperidol, Loxapine, Mesoridazine, Molindone,Ondansetron, Perphenazine, Piperacetazine, Thiopropazate, Thioridazine,Thiothixene, Trifluoperazine and Triflupromazine.

15. Anti-Ulcerative agents such as Enprostil and Misoprostol.

16. Anti-Viral agents such as Acyclovir, Rimantadine and Vidarabine.

17. Anxiolytic agents such as Buspirone, Benzodiazepines such asAlprazolam, Chlordiazepoxide, Clonazepam, Clorazepate, Diazepam,Flurazepam, Halazepam, Lorazepam, Oxazepam, Oxazolam, Prazepam andTriazolam.

18. β-Adrenergic agonist agents such as Albuterol, Carbuterol,Fenoterol, Metaproterenol, Rimiterol, Quinterenol, Salmefamol,Soterenol, Tratoquinol, Terbutaline and Terbuterol.

19. Bronchodilators such as Ephedrine derivatives including Epiniphrineand Isoproterenol, and Theophylline.

20. Cardioactive agents such as Atenolol, Benzydroflumethiazide,Bendroflumethiazide, Calcitonin, Captopril, Chlorothiazide, Clonidine,Dobutamine, Dopamine, Diltiazem, Enalapril, Enalaprilat, Gallopamil,Indomethacin, Isosorbide Dinitrate and Mononitate, Nicardipine,Nifedipine, Nitroglycerin, Papaverine, Prazosin, Procainamide,Propranolol, Prostaglandin E₁, Quinidine Sulfate, Timolol, andVerapamil.

21. α-Adrenergic agonist agents such as Phenylpropanolamine.

22. Cholinergic agents such as Acetylcholine, Arecoline, Bethanechol,Carbachol, Choline, Methacoline, Muscarine and Pilocarpine.

23. Estrogens such as Conjugated Estrogenic Hormones, Equilenin,Equilin, Esterified Estrogens, Estradiol, 17β-Estradiol, EstradiolBenzoate, 17β-Estradiol Valerate, Estradiol 17β-Cypionate, Estriol,Estrone, Estropipate, 17β-Ethinyl Estradiol and Mestranol.

24. Muscle relaxants such as Baclofen.

25. Narcotic antagonist agents such Nalmfene and Naloxone.

26. Progestational agents such as Chlormadinone and ChlormadinoneAcetate, Demegestone, Desogestrel, Dimethisterone, Dydrogesterone,Ethinylestrenol, Ethisterone, Ethynodiol and Ethynodiol Diacetate,Gestodene, 17α-Hydroxyprogesterone, Hydroxygesterone Caproate,Medroxyprogesterone and Medroxyprogesterone Acetate, Megestrol Acetate,Melengestrol, Norethindrone and Norethidrone Acetate, Norethynodrel,Norgesterone, Norgestrel, 19-Norprogesterone, Progesterone, Promegestoneand esters thereof. Free base forms of drugs which have a greateraffinity for the acid (carboxyl) functional group in a carboxylfunctional acrylic-based polymer are preferred in some applications.

For most drugs, their passage through the skin or mucosa will be therate-limiting step in delivery. Thus, the amount of drug and the rate ofrelease is typically selected so as to provide delivery characterized bya pseudo-zero order time dependency for a prolonged period of time. Theminimum amount of drug in the system is selected based on the amount ofdrug which passes through the skin or mucosa in the time span for whichthe device is to provide a therapeutically effective amount. Generally,the amount of drug in the transdermal system can vary from about 0.1 to40% by weight, preferably 0.5 to 30% by weight, and optimally 1-20%weight per cent, based on the total dry weight of the agent-carriercomposition.

The inventors have found that by separately preparing and processing thedrug carrier composition and the non-drug loaded polymeric or adhesivecoating (applied to either the backing or the release liner), greaterflexibility can be achieved in controlling delivery rates and profiles.For example, typical carrier compositions prepared with acrylic-basedpolymers or blend of polymers for a transdermal delivery device requirecoat weights of about 10 mg/cm² to achieve the desired drug loading andadhesive characteristics. In the present invention, the coat weight of acarrier composition for delivering at least one drug at a similar fluxmay be reduced to about 5 mg/cm², or about one-half the coat weight ofprior systems.

The polymeric coating 18 may comprise one or more of the polymers oradhesives described with reference to the drug carrier composition,generally with higher percent solids, but contain no active agent duringits exposure to elevated temperatures for solvent removal prior to beingaffixed to the drug carrier composition. Preferred are non-functional,acrylic-based adhesives. The polymeric coating is disposed on either thebacking or release liner and generally at a thickness so that the coatweight ranges from about 2.5 mg/cm² to about 15 mg/cm².

Once affixed to the carrier composition, the non-drug loaded polymericor adhesive coating serves to absorb or attract and retain amounts ofdrug from the drug carrier composition, and subsequently release drugupon topical application of the transdermal system. This process furtherallows for potentially higher drug loading in the carrier composition,where desired or needed, for example to deliver drugs requiring higheramounts to be therapeutically effective and/or to delivertherapeutically effective amounts over a longer period of delivery,since any excess solubilized drug or supersaturated or highlyconcentrated drug will be absorbed or drawn away thereby permitting thecarrier composition to maintain its desired adhesive properties whilestill providing desired permeation rate and profile to be achieved.

The polymeric coating can further be prepared to selectively control thedesired delivery rate, onset and profile for the drug by varying certainother physical characteristics. As demonstrated in the examplesemploying an acrylic-based adhesive coating, the delivery rate, onset ofdelivery (lag time) and delivery profile of estradiol from thetransdermal system may be selectively modulated by one or more of (a)increasing or decreasing the thickness or coat weight of per cm² (asapplied to the backing or release liner of the system) or (b)manipulating the moiety or functionality.

While one or more acrylic-based adhesives are preferred for use as thenon-drug loaded coating, other polymers, alone or in combination, may beused provided such polymers have the ability to (a) incorporate and holddrug from the drug-loaded carrier composition after manufacture, (b)maintain contact/adhesion to both the carrier composition and either thebacking film/layer or the release liner, preferably without the use ofadditional adhesives, (c) not degrade or interfere with stability of thedrug, and (d) release or deliver the drug to the skin or mucosa aftertopical application of the transdermal system.

In certain embodiments of the invention, an enhancer can be incorporatedinto either the carrier composition or the polymeric coating, or both.The term “enhancers” as used herein refers to substances used toincrease permeability and/or accelerate the delivery of an active agentthrough the skin or mucosa, and include monhydric alcohols such asethyl, isopropyl, butyl and benzyl alcohols; or dihydric alcohols suchas ethylene glycol, diethylene glycol, or propylene glycol, dipropyleneglycol and trimethylene glycol; or polyhydric alcohols such as glycerin,sorbitol and polyethylene glycol, which enhance drug solubility;polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl,oleyl and stearly) including polyoxyethylene (4) lauryl ether,polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ethercommercially available under the trademark BRIJ® 30, 93 and 97 from ICIAmericas, Inc., and BRIJ® 35, 52, 56, 58, 72, 76, 78, 92, 96, 700 and721; vegetable, animal and fish fats and oils such as cotton seed, corn,safflower, olive and castor oils, squalene, and lanolin; fatty acidesters such as propyl oleate, decyl oleate, isopropyl palmitate, glycolpalmitate, glycol laurate, dodecyl myristate, isopropyl myristate andglycol stearate which enhance drug diffusibility; fatty acid alcoholssuch as oleyl alcohol and its derivatives; fatty acid amides such asoleamide and its derivatives; urea and urea derivatives such asallantoin which affect the ability of keratin to retain moisture; polarsolvents such as dimethyldecylphosphoxide, methyloctylsulfoxide,dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide,dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide whichaffect keratin permeability; salicylic acid which softens the keratin;amino acids which are penetration assistants; benzyl nicotinate which isa hair follicle opener; and higher molecular weight aliphaticsurfactants such as lauryl sulfate salts which change the surface stateof the skin and drugs administered and esters of sorbitol and sorbitolanhydride such as polysorbate 20 commercially available under thetrademark Tween® 20 from ICI Americas, Inc., as well as otherpolysorbates such as 21, 40, 60, 61, 65, 80, 81, and 85. Other suitableenhancers include oleic and linoleic acids, triacetin, ascorbic acid,panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate,tocopheryl linoleate. If enhancers are incorporated into the transdermalsystem, the amount typically ranges up to about 30%, and preferably fromabout 0.1% to about 15%, by weight based on the dry weight of the totalcarrier composition.

Enhancers for use in the drug carrier composition and polymeric coatingmay be selected differently in cases where it might be desirable to usediffering processing conditions for the drug carrier composition andpolymeric coating, for example to prevent drug loss where high or excessdrug concentration or loading in the carrier composition. Enhancers foruse with the polymeric coating may be selected with sufficiently highboiling points or lower volatile reactivity within the coating towithstand prolonged exposure to elevated processing temperaturesemployed to drive off the solvents therein, and include monovalent,saturated and unsaturated aliphatic and cycloaliphatic alcohols having 6to 12 carbon atoms such as cyclohexanol, lauryl alcohol and the like;aliphatic and cycloaliphatic hydrocarbons such as mineral oils;cycloaliphatic and aromatic aldehydes and ketones such as cyclohexanone;N,N-di (lower alkyl) acetamides such as N,N-diethyl acetamide,N,N-dimethyl acetamide, N-(2-hydroxyethyl) acetamide, and the like;aliphatic and cycloaliphatic esters such as isopropyl myristate andlauricidin; N,N-di (lower alkyl) sulfoxides such as decylmethylsulfoxide; essential oils; nitrated aliphatic and cycloaliphatichydrocarbons such as N-methyl-2-Pyrrolidone, Azone; salicylates,polyalkylene glycol silicates; aliphatic acids such as oleic acid andlauric acid, terpenes such as cineole, surfactants such as sodium laurylsulfate, siloxanes such as hexamethyl siloxane; polyethylene glycols,polypropylene glycols, and polyether polyols, epoxidized linseed oils,simple liquid esters, and the like, alone or in combination.

On the other hand, enhancers selected for use with the drug carriercomposition may be those with lower boiling points or higher relativevolatility or reactivity within the carrier composition since exposureto elevated processing temperatures is decreased, and therefore theirloss, similar to drug loss, is decreased. Such enhancers are well knownin the art and examples include alcohols, propylene glycol, dipropyleneglycol, butylene glycol, m-pyrol, with propylene glycol being preferred.

In addition to enhancers, there may also be incorporated variouspharmaceutically acceptable additives and excipients available to thoseskilled in the art. These additives include tackifying agents such asaliphatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons,aromatic hydrocarbons, substituted aromatic hydrocarbons, hydrogenatedesters, polyterpenes, silicone fluid, mineral oil and hydrogenated woodrosins. Additional additives include binders such as lecithin which“bind” the other ingredients, or rheological agents (thickeners)containing silicone such as fumed silica, reagent grade sand,precipitated silica, amorphous silica, colloidal silicon dioxide, fusedsilica, silica gel, quartz and particulate siliceous materialscommercially available as Syloid®, Cabosil®, Aerosil®, and Whitelite®,for purposes of enhancing the uniform consistency or continuous phase ofthe composition or coating. Other additives and excipients includediluents, stabilizers, fillers, clays, buffering agents, biocides,humectants, anti-irritants, antioxidants, preservatives, plasticizingagents, cross-linking agents, flavoring agents, colorants, pigments andthe like. Such substances can be present in any amount sufficient toimpart the desired properties to the composition or coating. Suchadditives or excipients are typically used in amounts up to 25%, andpreferably from about 0.1% to about 10%, by weight based on the dryweight of the total carrier or polymeric coating composition.

Transdermal system 10 further employs release liners orremovable/peelable covers and backings to protect and/or anchor thesystem or its components during manufacturing as described herein, orthereafter, and to enable handling and transportation.

The release liner is typically impermeable and occlusive, and must becompatible with the particular polymers or active agents so as not tointerfere with the composition's ultimate application and therapeuticeffect. Some suitable materials that can be used, singularly, incombination, as laminates, films, or as coextrusions, to form therelease liner are well known in the art. When the release liner iscomposed of a material which typically does not readily release (i.e.,is not easily removed or separated from the coating or composition towhich it is affixed), for example paper, a releasable material such as asilicone, Teflon®, or the like may be applied to the surface by anyconventional means. Preferred release liners are films commerciallyavailable from DuPont, Wilmington, Del., under the trademarks Mylar®,and fluropolymer (silicone) coated films commercially available fromRexam Release, Oak Brook, Ill. under the trademarks FL2000® andMRL2000®, and from 3M Corporation, St. Paul, Minn. Sold under thetrademarks ScotchPak® such as 1022.

The backing is typically moisture impermeable and flexible but should becompatible with the particular polymers or active agents used so as notto interfere with the composition's ultimate application and therapeuticeffect. Some suitable materials that can be used, singularly, incombination, as laminates, films or as coextrusions, to form the backinglayer 20 are also well known in the art and include films or sheets ofpolyethylene, polyester, polypropylene, polyurethane, polyolefin,polyvinyl alcohol, polyvinyl chloride, polyvinylidene, polyamide, vinylacetate resins, BAREX®, ethylene/vinyl acetate copolymers,ethylene/ethylacrylate copolymers, metal-vapor deposited films or sheetsthereof, rubber sheets or films, expanded synthetic resin sheets orfilms, non-woven fabrics, fabrics, knitted fabrics, clothes, foils andpapers. The backing layer 20 may generally have a thickness in the rangeof 2 to 1000 micrometers. The backing layer 20 may be pigmented, forexample colored to either match with or conversely easily distinguishfrom the site of application, and/or contain printing, labeling andother means of identification and/or traceability of the transdermalunit or system itself. The backing layer 20 may further be made opaqueor substantially opaque (i.e., preventing light or certain energywavelengths from penetrating or passing through), such as bymetallization, fillers, inks, dyes and the like, for purposes ofprotecting photosensitive active agents from degradation and/orpreventing photoallergic reactions or irritations on the subject.

The drug carrier and polymeric coating comprising the present inventioncan be prepared in any manner known to those of skill in the art. In themanufacture of a transdermal system 10 according to the presentinvention, drug carrier composition layer 12 and the non-drug loadedpolymeric and/or adhesive coating 18 may be prepared and processedseparately, and then combined. It should be understood, however, that ifdrug or solvent loss is not critical to the formulation of thetransdermal system, drug carrier composition layer 12 and the non-drugloaded polymeric and/or adhesive coating 18 may be prepared separatelyand processed together.

One method of preparing transdermal system 10 is as follows:

1. Appropriate amounts of the polymer(s), adhesive(s), solvent(s),co-solvent(s), enhancer(s), additive(s) and/or excipient(s) are combinedand thoroughly and uniformly mixed together in a vessel to form thenon-drug loaded polymeric coating.

2. The polymeric coating is then transferred to a coating operationwhere it is cast onto a backing film/layer at a controlled specifiedthickness and exposed to elevated temperatures, such as in an oven, toremove the volatile processing solvents.

3. The polymeric coating is then laminated to a release liner applied tothe surface opposite the backing/layer and wound into rolls.

4. Appropriate amounts of drug(s), polymer(s), adhesive(s), solvent(s),co-solvent(s), enhancer(s), additive(s) and/or excipient(s) are combinedand thoroughly and uniformly mixed together in a vessel to form theactive agent carrier composition.

5. The composition is then transferred to a coating operation where itis cast onto a release liner at a controlled specified thickness andexposed to elevated temperatures, such as in an oven, to remove thevolatile processing solvents.

6. As depicted in FIG. 2, the release liner 22 that is affixed to thepolymeric coating 18 to form the backing composite 16 is then removedand affixed to the exposed surface of the drug carrier composition 12,and the laminated assembly is wound into rolls.

7. Thereafter, desired size and shape delivery systems 10 are preparedby die-cutting or the like, from the rolled laminate and then packaged.

Alternatively, the release liner 22 may not be necessary if both theagent-carrier composition 12 and backing composite 16 are producedconcomitantly, wherein attachment to each other could be performed afterprocessing of each individually, such as in an in-line process, therebyavoiding step 3 above. As described earlier, either the drug carriercomposition 12 or the polymeric coating 18 may be an adhesive orpressure-sensitive adhesive, allowing pressure lamination to each otherby their adhesive qualities. However, where a release liner 22 isemployed in the manufacturing steps, it is preferable to affix it to thepolymeric coating and not the drug carrier composition to prevent anyfurther drug loss that could occur from winding into rolls andsubsequent removal of such release liner, or the failure of releaseliner 22 to adhere to the drug carrier composition.

Additionally and alternatively, a separate adhesive may be used to (a)affix the backing composite 16 to the drug carrier composition 12 at thesurface opposite the release liner 15 and/or (b) affix the polymericcoating or the drug carrier composition, depending on which is to beused as the point of topical application to the skin or mucosa, toeither the backing film/layer or the release liner.

In certain other preferred embodiments, a non-woven drug permeablefilm/layer, such as a polyester film, may be interdisposed, such aspressure lamination, for structural support or ease of manufacturing(i.e., has no effect on controlling drug permeation or delivery) betweenthe non-drug loaded coating and the drug-loaded carrier composition.

In cases where it might be desirable to use differing processingconditions for the drug carrier composition and the polymeric coating,for example to prevent drug loss where there is high or excess drugconcentration or loading in the carrier composition, or where the drugdegrades by exposure to atmospheric air, or that employ use of volatileenhancers, particular care may need to be employed to avoid prolongedprocessing times or exposure to air during manufacturing. In thisregard, controlled manufacturing environments, for example employinglower temperatures or pressures, employing faster processing speedsduring exposure to the elevated temperature used to remove solvents,modifying atmospheric gases present (such reduced carbon dioxide levelsor using nitrogen in place of air), or modifying air or gas flow (suchas during oven drying to remove solvents) at various stages during theprocess, may also be necessary or desirable.

The order of the processing steps, the amount of the ingredients, andthe amount and time of agitation or mixing may be important processvariables which will depend on the specific polymers, active agents,solvents or co-solvents, enhancers and additives and excipients used inthe transdermal system. These factors can be adjusted by those skilledin the art, while keeping in mind the objects of achieving theinteraction between the drug carrier composition and the non-drug loadedcoating. It is believed that a number of other methods, for example,other methods of coating that are well-known in the art, such as Mayerrod, gravure, knife-over roll, extrusion, casting, calendaring andmolding, or changing the order of certain steps, can be carried out andwill also give desirable results.

Further details and examples of pressure-sensitive adhesives, enhancers,solvents, co-solvents, release liners, backing layers, and otheradditives, as well as transdermal systems generally, suitable inpracticing the invention are described in U.S. Pat. Nos. 5,474,787,5,958,446, 6,024,976, 6,562,363 and 60/488,928, all of which areassigned to Noven Pharmaceuticals, Inc. and incorporated herein byreference.

EXAMPLES

In the Examples as shown with respect to FIGS. 3-4, the effect ofvariations in the non-drug loaded coating are determined, indicating theeffective control of permeation rate, onset and profile thereby.Referring to the most preferred embodiment depicted in FIG. 1, while theExamples are directed to formulations using estradiol and anacrylic-based adhesive coating, it should be understood that similardrug modulation can be achieved with other active agents, and throughthe use of other polymers and system configurations as discussed.

All drug-loaded carrier compositions containing estradiol were preparedand coated onto a fluropolymer release liner and dried for 5 minutes atRT and 5 minutes in a 92° C. oven to produce a pressure-sensitiveadhesive carrier composition by dry weight of 20% acrylatepressure-sensitive adhesive (GMS 788), 56% silicone pressure-sensitiveadhesive (BIO-PSA-4502), 8% soluble povidone, 6% oleyl alcohol, 8%dipropylene glycol and 2% estradiol at coat weight of about 5 mg/cm².All studies were conducted relative to a control transdermal deliverysystem, that being an estrogen transdermal delivery system (Vivelle Dot®manufactured by the assignee of the instant invention, NovenPharmaceuticals, Inc.), having a known permeation rate, onset andprofile.

The non-drug loaded acrylic-based adhesive coatings were varied todetermine the effect of the non-drug loaded layer 18 on controllingpermeation rate and drug delivery profile of estradiol. As can be seenfrom the Examples and FIGS. 3-4, control of estradiol delivery profilecan be achieved by the use of different moieties in the acrylic polymerbacking, the coat weight of the acrylic backing film had a moresubstantial effect on the permeation rate of estradiol rather than thedelivery profile, and varying the thickness and/or moiety of the acrylicpolymer backing can modify the drug delivery profile and permeation rateof estradiol.

Determination of drug flux of the described formulations was conductedon a modified Franz Diffusion cell through a disc of stratum comeumobtained from human cadaver skin. The transdermal systems were die-cutand mounted on the disc, and placed on the cell, which contained anisotonic saline solution. The cells were stored at 32° C. for theduration of each flux study while having the solution stirred at aconstant rate of approximately 300 rpm. Samples (n=5) of the solutionwere taken at various time points over the study duration (9 hours), anddrug concentrations were determined by high pressure liquidchromatography.

Examples 1-3

In Examples 1-3, the three acrylic acrylic coated backings utilizeddifferent moieties of acrylic polymer in their composition: Example 1contains an acid functional moiety, Example 2 contains anon-functional/non-reactive moiety, and Example 3 contains a hydroxyl(—OH) functional moiety. The acrylic coating on the backing had a coatweight of 5.0 mg/cm² and was coated onto a polyester film. Thedrug-in-adhesive matrix had a coat weight of 5.0 mg/cm².

FIG. 3 illustrates the results for the three moieties of theacrylic-based polymer backings utilized. Acid functional and hydroxylfunctional acrylic polymer backings had a similar effect on the deliveryprofile of estradiol. The non-functional/non-reactive moiety in theacrylic backing exhibited a decrease in the delivery profile after 48hours of delivery compared to the acid functional and hydroxylfunctional acrylic backings.

Example 4-6

In Examples 4-6, a single acid functional acrylic polymer backingvarying the coat weight was utilized. Coat weights for the acrylicbacking were 2.5 mg/cm², 5.0 mg/cm², and 10.0 mg/cm² for Examples 4, 5,and 6, respectively. The results, set forth in FIG. 4, illustrate thatthe permeation rate decreases as the acid functional acrylic backingthickness increases although the drug delivery profile appears to remainthe same, at or near zero-order, for all three coat weights. Thedrug-in-adhesive matrix had a coat weight of 5.0 mg/cm².

The examples show that by tailoring the acrylic backing polymer throughchanges in moiety and thickness one can attain a desired permeation rateand delivery profile for estradiol. As the functional moiety andthickness change, the permeation rate and delivery profile can bechanged to create a transdermal patch with a multitude of deliveryprofiles and rates for a selected therapeutic target.

The above description and examples are only illustrative of preferredembodiments which achieve the objects, features, and advantages of thepresent invention, and it is not intended that the present invention belimited thereto.

1. A method of controlling the flux of a drug from a transdermal drugdelivery composition, comprising: preparing a composition comprising:(i) a backing layer; (ii) an adhesive coating layer comprising anacrylic-based polymer, wherein said adhesive coating layer does notinclude any drug at the time of preparation, and wherein a first surfaceof said adhesive coating layer is affixed to one surface of said backinglayer; (iii) a carrier composition layer comprising an acrylic-basedpolymer, wherein said carrier composition layer includes an excess drugconcentration, wherein said excess drug is present in a solidcrystalline form at the time of preparation, and wherein a first surfaceof said carrier composition layer is affixed to a second surface of saidadhesive coating layer; and (iv) a release liner affixed to a secondsurface of said carrier composition layer; wherein said adhesive coatinglayer is selected to control the flux of said drug from the transdermaldrug delivery composition.
 2. The method of claim 1, wherein the coatweight of said adhesive coating layer is selected to control the flux ofsaid drug from the transdermal drug delivery composition.
 3. The methodof claim 1, wherein said acrylic polymer of said adhesive coating layerhas a monomer content that is selected to control the flux of said drugfrom the transdermal drug delivery composition.
 4. The method of claim1, wherein said adhesive coating layer has a functionality that isselected to control the flux of said drug from the transdermal drugdelivery composition.
 5. The method according to claim 1, wherein saiddrug comprises estradiol.
 6. The method according to claim 1, whereinsaid carrier composition layer comprises a blend of at least oneacrylic-based polymer and at least one second polymer selected from thegroup consisting of silicone-based polymers, rubbers, gums,polyisobutylenes, polyvinylethers, polyurethanes, styrene blockcopolymers, styrene/butadiene polymers, polyether block amidecopolymers, ethylene/vinyl acetate copolymers, vinyl acetate basedadhesives, polyvinylypyrrolidones and bioadhesives.
 7. The methodaccording to claim 6, wherein said at least one second polymer of saidcarrier composition layer includes a silicone-based polymer.
 8. Themethod according to claim 6, wherein the acrylic-based polymer of saidcarrier composition layer comprises from about 2% to about 95% of thetotal dry weight of the carrier composition layer.
 9. The methodaccording to claim 1, wherein said acrylic-based polymer of said carriercomposition layer-comprises from about 2% to about 95% of the total dryweight of the carrier composition layer.
 10. The method according toclaim 9, wherein said acrylic-based polymer of said carrier compositionlayer comprises from about 2% to about 85% of the total dry weight ofthe carrier composition layer.
 11. The method according to claim 1,wherein said carrier composition layer includes: (i) a firstacrylic-based polymer having a first functionality and a firstsolubility parameter for said drug; and (ii) a second acrylic-basedpolymer having a second functionality and solubility parameter for saiddrug, wherein the first and second functionalities differ in the amountand type of functional groups, to provide an acrylic-based polymercombination having a net functionality proportional to the ratio of thefirst and second acrylic based polymers used, and wherein said first andsecond acrylic-based polymers are present in proportions to provide anet solubility parameter for said drug.
 12. The method according toclaim 11, wherein the first acrylic-based polymer of said carriercomposition layer is present in an amount to provide a flux of said drugin the transdermal drug delivery composition which is greater than acomposition based solely on the second acrylic-based polymer.
 13. Themethod according to claim 12, wherein the amount of the secondacrylic-based polymer in said carrier composition layer is in the rangeof 5-95 weight % and the amount of the first acrylic-based polymer is inthe range of 95 to 5% by weight, all based on the total dry weight ofthe first and second acrylic-based polymers.
 14. The method according toclaim 13, wherein the amount of the second acrylic-based polymer in saidcarrier composition layer is in the range of 20-75 weight % and theamount of the first acrylic-based polymer is in the range of 75 to 20%by weight, all based on the total dry weight of the first and secondacrylic-based polymers.
 15. The method according to claim 11, whereinthe first acrylic based polymer of said carrier composition layer hassubstantially no functional groups and the second acrylic-based polymerhas predetermined functional groups.
 16. The method according to claim15, wherein the second acrylic-based polymer of said carrier compositionlayer has carboxyl and/or hydroxy functional groups.
 17. The methodaccording to claim 15, wherein the second acrylic-based polymer of saidcarrier composition layer is present in an amount to provide anincreased saturation concentration of said drug in the transdermal drugdelivery composition which is greater than that of a composition basedsolely on the first acrylic-based polymer.
 18. The method according toclaim 11, wherein the functional groups are provided by monomer unitscontaining functional groups which are incorporated into the secondacrylic-based polymer in an amount of from 0.1 to 20% by weight, basedon the dry weight of the second acrylic-based polymer.
 19. The methodaccording to claim 18, wherein the functional monomers are incorporatedinto the second acrylic-based polymer of said carrier composition layerin an amount of from 0.1 to 8% by weight, based on the dry weight of thesecond acrylic-based polymer.
 20. The method according to claim 11,wherein the first acrylic-based polymer of said carrier compositionlayer contains hydroxy functional groups and the second acrylic-basedpolymer contains carboxy functional groups.
 21. The method according toclaim 11, wherein the polymer components of the carrier compositionlayer consist essentially of only the first and second acrylic-basedpolymers.
 22. The method according to claim 11, wherein the secondacrylic-based polymer of said carrier composition layer includescarboxyl functional groups.
 23. The method according to claim 22,wherein the carboxyl functional acrylic-based polymer includes 0.1 to10% by weight of carboxyl functional monomer units.
 24. The methodaccording to claim 23, wherein the carboxyl functional acrylic-basedpolymer is a crosslinked vinyl acetate acrylic-based polymer.
 25. Themethod according to claim 3, wherein said adhesive coating layerincludes: (i) a first acrylic-based polymer having a firstfunctionality; and (ii) a second acrylic-based polymer having a secondfunctionality, wherein the first and second functionalities differ inthe amount and type of functional groups, to provide an acrylic-basedpolymer combination having a net functionality proportional to the ratioof the first and second acrylic-based polymers used.
 26. The methodaccording to claim 25, wherein the amount of the second acrylic-basedpolymer of the adhesive coating layer is in the range of 5-95 weight %and the amount of the first acrylic-based polymer is in the range of 95to 5% by weight, all based on the total dry weight of the first andsecond acrylic-based polymers.
 27. The method according to claim 25,wherein the amount of the second acrylic-based polymer of the adhesivecoating layer is in the range of 20-75 weight % and the amount of thefirst acrylic-based polymer is in the range of 75 to 20% by weight, allbased on the total dry weight of the first and second acrylic-basedpolymers.
 28. The method according to claim 25, wherein the firstacrylic-based polymer of the adhesive coating layer has substantially nofunctional groups and the second acrylic-based polymer has predeterminedfunctional groups.
 29. The method according to claim 28, wherein thesecond acrylic-based polymer of the adhesive coating layer has carboxyland/or hydroxy functional groups.
 30. The method according to claim 25,wherein the functional groups are provided by monomer units containingfunctional groups which are incorporated into the second acrylic-basedpolymer in an amount of from 0.1 to 20% by weight, based on the dryweight of the second acrylic-based polymer.
 31. The method according toclaim 30, wherein the functional monomers are incorporated into thesecond acrylic-based polymer in an amount of from 0.1 to 8% by weight,based on the dry weight of the second acrylic-based polymer.
 32. Themethod according to claim 25, wherein the polymer components of theadhesive coating layer consist essentially of only the first and secondacrylic-based polymers.
 33. The method according to claim 25, whereinthe second acrylic-based polymer of the adhesive coating layer includescarboxyl functional groups.
 34. The method according to claim 33,wherein the carboxyl functional acrylic-based polymer includes 0.1 to10% by weight of carboxyl functional monomer units.
 35. The methodaccording to claim 34, wherein the carboxyl functional acrylic-basedpolymer is a crosslinked vinyl acetate acrylic-based polymer.
 36. Themethod according to claim 1, wherein said adhesive coating layerincludes a blend of: (i) an acrylic-based polymer; and (ii) at least onesecond polymer selected from the group consisting of silicone-basedpolymers, rubbers, gums, polyisobutylenes, polyvinylethers,polyurethanes, styrene block copolymers, styrene/butadiene polymers,polyether block amide copolymers, ethylene/vinyl acetate copolymers,vinyl acetate based adhesives, and bioadhesives.
 37. The methodaccording to claim 36, wherein said second polymer includes asilicone-based polymer.
 38. The method according to claim 2, whereinsaid adhesive coating layer has a coat weight of from about 2.5 to about15 mg/cm².
 39. The method according to claim 2, wherein said adhesivecoating layer has a coat weight of from about 2.5 to about 7.5 mg/cm².40. The method according to claim 2, wherein said adhesive coating layerhas a coat weight of at least 5 mg/cm².
 41. The method according toclaim 1, wherein said acrylic-based polymer of the adhesive coatinglayer comprises an acrylate or alkyl acrylate monomer selected from thegroup consisting of acrylic acid, methacrylic acid, methyl acrylate,methyl methacrylate, butyl acrylate, butyl methacrylate, hexyl acrylate,hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate,isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate,2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecylacrylate, dodecyl methacrylate, tridecyl acrylate, and tridecylmethacrylate.
 42. The method according to claim 1, wherein saidacrylic-based polymer of the adhesive coating layer comprises afunctional monomer selected from the group consisting of acrylic acid,methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate,hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tertbutylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate.